Activated but not resting T cells can cross the blood brain barrier and initiate a T cell mediated autoimmune response against the central nervous system myelin. Previous studies have demonstrated that human myelin basic protein (MBP) specific T cell clones are activated by viral peptides that are quite distinct in their primary sequence from the MBP peptide. The goal of this project is to examine the pathogenicity of such viral peptides and to define the structural basis for the recognition of viral peptides by MBP specific T cell receptors (TCRs). The encephalitogenicity of viral peptides will be examined for a conserved, immunodominant T cell epitope of human MBP (residues 88- 102) that induces experimental autoimmune encephalomyelitis in several well established animal models. The induction of CNS autoimmunity will be examined by transfer of virus specific T cell lines from virus- infected to naive animals and by immunization with viral peptides that activate MBP(88-102) specific T cells. The activation of human MBP specific T cells by virus infected cells will be examined, in an effort to determine which viruses activate MBP specific T cells from patients with multiple sclerosis and other inflammatory CNS diseases. The activation of autoreactive T cells by foreign peptides may be important for the induction of T cell mediated autoimmunity by microbial antigens. However, the sequence diversity of peptides that are recognized by autoreactive T cell clones is not known, since previous approaches have assumed that such microbial peptides would only represent minor variations of self-pep tide sequences. Peptides that are recognized by MBP specific TCRs will be sought using a peptide library in which all peptide positions, except two MHC anchor residues, will be randomized. To investigate the structural basis for the recognition of DR/peptide complexes by a TCR, soluble MBP specific TCRs will be expressed using an coli expression system that recently allowed the crystallization of a MHC class I/peptide/TCR complex. MBP specific TCRs will be co-crystallized with DR2/MBP and other cross-reactive peptides to examine the structural basis for TCR cross-reactivity by X-ray crystallography.